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Purpose of Review: Our understanding of the interactions of genes and pathways during heart development continues to expand with our knowledge of the genetic basis of congenital heart disease. Along with the discovery of specific genes that cause lesions, recent research has focused on the interactions of some previously identified genes. This review focuses on the progress made during the last year., Recent Findings: T-box, NK, and GATA transcription factors have known associations with a variety of syndromic and isolated congenital heart defects. Discovery of novel interactions of GATA and T-box transcription factors highlights the direction of recent research. In addition, the critical yet somewhat redundant roles of nkx2.5 and nkx2.7, along with the interaction of nkx2.7 with tbx20, have been elucidated. The contributions of still other transcription factor classes are being elucidated. Further understanding of 22q11.2 deletion and microduplication syndromes and their genetic interactions has also been studied. Recent work also highlights PTPN11 and NOTCH1 in Noonan syndrome., Summary: The recent developments in the genetics of congenital heart disease are reviewed. In many cases, it is the novel interactions of previously known genes that highlight this year's developments. These interactions will ultimately lead to better understanding of downstream transcriptional or signaling pathways.

Diseases of the cardiovascular system that cause sudden cardiac deaths are often caused by lethal arrhythmias that originate from defects in the cardiac conduction system. Development of the cardiac conduction system is a complex biological process that can be wrought with problems. Although several genes involved in mature conduction system function have been identified, their association with development of specific subcomponents of the cardiac conduction system remains challenging. Several transcription factors, including homeodomain proteins and T-box proteins, are essential for cardiac conduction system morphogenesis and activation or repression of key regulatory genes. In addition, several transcription factors modify expression of genes encoding the ion channel proteins that contribute to the electrophysiological properties of the conduction system and govern contraction of the surrounding myocardium. Loss of transcriptional regulation during cardiac development has detrimental effects on cardiogenesis that may lead to arrhythmias. Human genetic mutations in some of these transcription factors have been identified and are known to cause congenital heart diseases that include cardiac conduction system malformations. In this review, we summarize the contributions of several key transcription factors to specification, patterning, maturation, and function of the cardiac conduction system. Further analysis of the molecular programs involved in this process should lead to improved diagnosis and therapy of conduction system disease.

Studies the role and different interactions of TBX5, a T-box containing transcription factor in forelimb and heart development, in human morphogenesis. Identification of the roles of TBX5 by mutations that cause Holt-Oram syndrome; Materials and methods; Results and discussion.

Reports on the results of a study of a mouse model of Holt-Oram syndrome, which has been associated with mutations in the T-box transcription factor TBX5. Its function; How mutations in it can cause disease; Results of previous studies; Effects of experimental changes in TBX5 expression on heart and limb development in various species; Influence of genetic background on disease manifestations; Importance of considering species-specific gene expression patterns; Conclusions.

The TBX5 transcription factor is required for normal cardiogenesis, and human TBX5 mutations cause congenital heart defects. Previous studies have shown that TBX5 can localize to cellular nuclei during embryogenesis and have suggested that altered nuclear localization may contribute to disease pathogenesis. Current analyses suggest that TBX5 nuclear localization is not uniform during organogenesis. To determine the biochemical mechanisms underlying TBX5 nuclear import, we performed site-directed mutagenesis of human TBX5. We identified two distinct nuclear localization signals in TBX5, one monopartite and one bipartite. While each is insufficient to promote complete TBX5 nuclear localization, they act cooperatively to do so. These sequences are evolutionarily conserved and have cognates in other T–box gene family members. [Copyright &y& Elsevier]